Developing new strategies to treat drug addiction requires a detailed understanding of how biomolecules are up and down regulated in response to a drug dose within specific regions of an organ, such as the brain. MALDI imaging mass spectrometry is a powerful tool that can give a biomolecular image map of tissue slices at unprecedented levels of molecular detail. A principal challenge of the technique is determining what components of a tissue give rise to the vast number of biomolecule that are observed for each laser shot (i.e. pixel) in the MALDI image. Here we propose targeting nanoparticles that can function as a MALDI matrix to specific cells or cell receptors. By localizing the matrix to a specific cell type or tissue region, only biomolecules in the vicinity of the nanoparticle matrix will be detected. By eliminating the formation of biomolecular ions from non-specific components of the tissue, the complexity of the molecular signal will be dramatically reduced allowing for the detection of lower abundance biomolecules in or near cells of interest. This technique is applicable for the analysis of both in-vitro tissue analysis and in-vivo studies where the functionalized nanoparticles are introduced directly into the tissue of interest. When used in conjunction with 2D ion separation techniques such as ion mobility time-of-flight mass spectrometry, this innovative technique will generate a focused biomolecular image map that can identify the biological response to drugs of abuse and lead to a new understanding of the molecular basi of addiction. PUBLIC HEALTH RELEVANCE: MALDI imaging mass spectrometry is a tool that can create a spatial map of the complex molecular makeup of tissues. One of the challenges of this emerging technology is how to deconvolute what tissue components give rise to particular biomolecular ions that are detected at a given location. By utilizing functionalized nanoparticles as a MALDI matrix, researchers will be able to monitor changes to biomolecules in and around specific cells or regions of a tissue as a function of drug exposure. Because the MALDI- MS signal is isolated to regions where the matrix is targeted, only molecular ions near the area of interest will be identified providing a powerful method of observing changes to a particular area of a tissue.